Biomedical imaging, such as magnetic resonance imaging (MRI), is a compelling imaging method as it allows peering into body with non-ionizing radiation. The images thus acquired enable the diagnosis and treatment of conditions that were previously revealed only by the scalpel. Generating new nanoscale imaging agents that can provide precise and high contrast views of lesions that would guide focused and effective treatment is certainly going to benefit biomedical imaging.
Multimodal nanoparticles are great vehicles with which to achieve simultaneous targeting, imaging, and drug delivery, an important goal in modern pharmacology (BHANU P. S. CHAUHAN: HYBRID NANOMATERIALS: SYNTHESIS, CHARACTERIZATION, AND APPLICATIONS, (John Wiley & Sons, Hoboken, N.J., 2011)). As part of this effort, an MRI imaging agent comprised of gadolinium complexes has recently been assembled on the surface of silver nanoparticles (Siddiqui et al., J. Colloid Interf. Sci. 337:88 (2009)). Noble metal NPs have been used in the development of multifunctional agents for the diagnosis and/or treatment of disease, because noble nanoparticles such as gold and silver nanoparticles are easy to synthesize. Such particles can be made multifunctional by supporting moieties anchored on their surface.
However, certain drawbacks exist in the use of noble metal particles for routine clinical use. For instance, these particles are expensive, and the use of these particles is inefficient because of an unused interior volume. Moreover, metal particles above 5-8 nm diameters are cleared only slowly through a hepatic pathway.
Solid lipid nanoparticles (SLNs) offer an important alternative for the formation of multimodal theranostic agents (Lammers et al., Acc. Chem. Res. 44(10):1029 (2011); Andreozzi et al., Bioconjugate Chem. 22:808 (2011)). They have certain characteristics that suit them for combined drug delivery and diagnostics (Muller et al., Eur. J. Pharm. Biopharm. 50:161 (2000)). Gd-containing SLNs has been reported as MRI contrast agents (Morel et al., Eur. J. Pharm. Biopharm. 45:157 (1998)). In that report, the uptake of gadolinium diethylenetriamine-N,N,N′,N″N″-pentaacetate (GdDTPA) and gadolinium tetraazacyclododecanetetraacetic acid (GdDOTA) to form the contrast agents was described, but the question of the contrast agent's location in relation to the surface of the SLN particle was left open. As a result, the mechanisms of contrast enhancement by Gd-containing SLNs could not be specified. In this type of particle, the subsurface/surface location of the contrast agent determines the degree to which proton spin relaxation of water is due to inner sphere, T1 relaxation (surface) or outer sphere T1 and T2, or susceptibility relaxation (subsurface) (Fossheim et al., J. Magn. Reson. Imaging 7:251 (1997)). In a follow-up study, a lipid with a polar GdDTPA headgroup was embedded in an SLN surface with GdDTPA confined to the surface (Zhu et al., J. Nanosci. Nanotechnol. 6:996 (2006)). A more recent paper describes the incorporation of the [GdDTPA]2− complex within an SLN core for magnetic resonance colonography. The latter particles were prepared in a miniemulsion in which [GdDTPA]2− was introduced in an aqueous phase that also contained monostearin (Sun et al., Magn. Reson. Med. 65:673 (2011)). It has also been described that the incorporation of neutral gadolinium acetylacetonate (GdAcAc) in SLNs, generated by nanotemplate engineering, can be used for crossing the blood brain barrier in neutron capture therapy of brain lesions (Oyewumi & Mumper, Bioconjugate Chem. 13:1328 (2002)).
The SLN platform has been found advantageous in the above studies from a clinical perspective because of its nanoscale size, biocompatibility, and biodegradation properties that aid clearance. However, the application of SLNs as imaging agents, possibly combined with drug release as theranostic agents, still has not been well developed.
In the United States, MRI contrast agents employ the DTPA ligand and its derivatives to coordinate the contrast-inducing ion Gd3+. DTPA is constructed from a diethylene triamine backbone. One attractive feature of DTPA is the ease with which it can be chemically modified to adjust its pharmacokinetics and biodistribution. However, GdDTPA with a stability constant of 1022 M−1 has a significant toxicological drawback. It has been shown to induce nephrogentic systemic fibrosis (NSF) a condition that is sometimes fatal resulting from the release of Gd3+ ions due to renal insufficiency (see Bongartz, Magn. Reson. Mater. Phy. 20:57 (2007), which is hereby incorporated by reference in its entirety). GdDOTA is more stable by several orders of magnitude with a stability of constant of 1028 M−1 (see Magerstadt et al., Magnet. Reson. Med. 3:808 (1986), which is hereby incorporated by reference in its entirety). What is therefore needed is a GdDOTA-based agent that contains functional groups based on DOTA ligands that enables the compositions to be useful in MRI applications. This invention answers that need.